Aromatic heterocyclic compounds and their use as anti-inflammatory agents

ABSTRACT

Novel aromatic heterocyclic compounds inhibit cytokines production involved in immunoregulation and inflammation such as interleukin-1 and tumor necrosis factor production. The compounds are therefore useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 09/461,446filed Dec. 14, 1999 now U.S. Pat. No. 6,228,881 which is a divisional ofSer. No. 09/181,743, filed Oct. 29, 1998, now U.S. Pat. No. 6,080,763,which claims priority from Provisional application Ser. No. 60/064,102,filed Nov. 3, 1997.

TECHNICAL FIELD OF THE INVENTION

The invention relates to aromatic heterocyclic compounds which inhibitthe release of inflammatory cytokines such as interleukin-1 and tumornecrosis factor from cells and are thus useful for treating diseases andpathological conditions involving inflammation such as chronicinflammatory disease. The invention also relates to processes forpreparing such compounds and pharmaceutical compositions comprisingthem.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines. These, along with several other related molecules, mediatethe inflammatory response associated with the immunological recognitionof infectious agents. The inflammatory response plays an important rolein limiting and controlling pathogenic infections.

Elevated levels of proinflammatory cytokines are associated with anumber of diseases of autoimmunity such as toxic shock syndrome,rheumatoid arthritis, osteoarthritis, diabetes and inflammatory boweldisease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). Inthese diseases, chronic elevation of inflammation exacerbates or causesmuch of the pathophysiology observed. For example, rheumatoid synovialtissue becomes invaded with inflammatory cells that result indestruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest.Med. 43: 28-38). An important and accepted therapeutic approach forpotential drug intervention in these diseases is the reduction ofproinflammatory cytokines such as TNF (also referred to in its secreted,cell-free form termed TNFα) and IL- 1β. A number of anti-cytokinetherapies are currently in clinical trials. Efficacy has beendemonstrated with a monoclonal antibody directed against TNF in a numberof autoimmune diseases (Heath, P., “CDP571: An Engineered Human IgG4Anti-TNFα Antibody” IBC Meeting on Cytokine Antagonists, Philadelphia,Pa., Apr. 24-5, 1997). These include the treatment of rheumatoidarthritis, Crohn's disease and ulcerative colitis (Rankin, E. C. C., etal., 1997, British J. Rheum. 35: 334-342 and Stack, W. A., et al., 1997,Lancet 349: 521-524). The monoclonal antibody is thought to function bybinding to both soluble TNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).

IL-1 has been implicated as an immunological effector molecule in alarge number of disease processes. IL-1 receptor antagonist (IL-1ra) hadbeen examined in human clinical trials. Efficacy has been demonstratedfor the treatment of rheumatoid arthritis (Antril, Amgen). In a phaseIII human clinical trial IL-1ra reduced the mortality rate in patientswith septic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitisshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. I1-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24). Elevation of several cytokines havebeen demonstrated during active inflammatory bowel disease (IBD). Amucosal imbalance of intestinal IL-1 and IL-1ra is present in patientswith IBD. Insufficient production of endogenous IL-1ra may contribute tothe pathogenesis of IBD (Cominelli, et al., 1996, Aliment PharmacolTher. 10, 49). Alzheimer disease is characterized by the presence ofbeta-amyloid protein deposits, neurofibrillary tangles and cholinergicdysfunction throughout the hippocampal region. The structural andmetabolic damage found in Alzheimer disease is due to a sustainedelevation of IL-1 (Holden, et al., 1995, Med Hypootheses 45, 559). Arole for IL-1 in the pathogenesis of human immunodeficiency virus (HIV)has been identified. IL-1ra showed a clear relationship to acuteinflammatory events as well as to the different disease stages in thepathophysiology of HIV infection (Kreuzer, et al., 1997, Clin ExpImmunol. 109, 54). IL-1 and TNF are both involved in periodontaldisease. The distructive process associated with peridontal disease maybe due to a disregulation of both IL-1 and TNF (Howells, 1995, Oral Dis.1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.TNFα has also been implicated in cachexia and muscle degradation,associated with HIV infection (Lahdiverta et al., 1988, Amer. J. Med.,85, 289). Obesity is associated with an increase incidence of infection,diabetes and cardiovascular disease. Abnormalities in TNFα expressionhave been noted for each of the above conditions (Loffreda, et al.,1998, FASEB J. 12, 57). It has been proposed that elevated levels ofTNFα are involved in other eating related disorders such as anorexia andbulimia nervosa. Pathophysiological parallels are drawn between anorexianervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47,423). An inhibitor of TNFα production, HU-211, was shown to improve theoutcome of closed brain injury in an experimental model (Shohami, etal., 1997, J Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. In consequence, IL-8 has a role in acuterespiratory response syndrome (ARDS) and in cerebral reperfusion injury(Matsumoto, et al., 1997, Journal ofLeukocyte Biology 62: 581). Blockingantibodies against IL-8 have demonstrated a role for IL-8 in theneutrophil associated tissue injury in acute inflammation (Harada etal., 1996: Molecular Medicine Today 2: 482). Rhinovirus triggers theproduction of various proinflammatory cytokines, predominantly IL-8,which results in symptomatic illnesses such as acute rhinitis (Wintheret al., 1998, Am J Rhinol. 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia andreperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dememtia complex, Alzheimersdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including burn-woundhealing, skin-graft resolutiona as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62: 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, J R CollPhysicians Lond 32, 56).

Interferon γ (IFN γ) has been implicated in a number of diseases. It hasbeen associated with increased collagen deposition that is a centralhistopathological feature of graft-versus-host disease (Parkman, 1998,Curr Opin Hematol. 5, 22). Following kidney transplantation, a patientwas diagnosed with acute myelogenous leukemia. Retrospective analysis ofperipheral blood cytokines revealed elevated levels of GM-CSF and IFN γ.These elevated levels coincided with a rise in peripheral blood whitecell count (Burke, et al., 1995, LeukLymphoma. 19, 173). The developmentof insulin-dependent diabetes (Type 1) can be correlated with theaccumulation in pancreatic islet cells of T-cells producing IFN γ(Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γ along with TNF,IL-2 and IL-6 lead to the activation of most peripheral T-cells prior tothe development of lesions in the central nervous system for diseasessuch as multiple sclerosis (MS) and AIDS dementia complex (Martino etal., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result inarterial disease that can lead to cardiac and cerebral infarction. Manyactivated immune cells are present in these lesions, mainly T-cells andmacrophages. These cells produce large amounts of proinflammatorycytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to beinvolved in promoting apoptosis or programmed cell death of thesurrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Areduced production of IFN γ is associated with onset of allergic diseasein infants (Warner et al., 1997, Pediatr Allergy Immunol. 8, 5).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dernatitis (Szepietowski, et al.,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 261). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:the rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN γ is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilboum, et al., 1997, Dis Mon. 43, 277). IFN γ isrequired for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43).Treatment of patients with IFN has demonstrated efficacy in a number ofdiseases including Behcet's disease which is a multisystem vasculitis.Interestingly in a small patient study for uveitis treatment with IFN γwas essentially ineffective (Kotter, et al., 1996, Ger J Ophthalmol. 5,92). A number of cancers can be treated with IFN γ, this includes thetreatment of multiple myeloma. Much of the effect is apparentlydependent on IL-6 which is a central myeloma growth factor (Palumbo etal., 1995, Leuk Lymphoma 18, 215). An elevated level of serum IgE isassociated with various atopic diseases such as bronchial asthma andatopic dermatitis. The level of IFN γ was negatively correlated withserum IgE suggesting a role for IFN γ in atopic patients (Teramoto etal, 1998, Clin Exp Allergy 28, 74).

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of various diseasestates. Some protein therapeutics are in late development or have beenapproved for use in particular diseases. Protein therapeutics are costlyto produce and have bioavailability and stability problems. Therefore aneed exists for new small molecule inhibitors of cytokine productionwith optimized efficacy, pharmacokinetic and safety profiles.

BRIEF DESCRIPTION OF THE INVENTION

The inventon provides novel compounds which inhibit the release ofinflammatory cytokines such as interleukin-1 and tumor necrosis factorfrom cells and which are thus useful for treating diseases andpathological conditions involving inflammation such as chronicinflammatory disease.

DETAILED DESCRIPTION OF THE INVENTION

In its broadest generic aspect, the invention provides novel compoundsof the formula I

wherein:

A is C or N;

B is C, N, O or S;

D is C, N or S;

E is C or N;

G is C, S or N;

X is S, O or NR₆;

Y is CHR₇ or N—H;

R₁ is selected from the group consisting of:

(a) C₃₋₁₀ branched alkyl, which is optionally partially or fullyhalogenated, and optionally substituted with one to three phenyl,naphthyl or heteroaryl groups (each such heteroaryl group beingindependently selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyland isothiazolyl), each such phenyl, naphthyl or heteroaryl group beingsubstituted with 0 to 5 groups selected from halogen, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, hydroxy, cyano, C₁₋₃ alkyloxy whichis optionally partially or fully halogenated, aminocarbonyl anddi(C₁₋₃)alkylaminocarbonyl;

(b) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which cycloalkyl group is optionallypartially or fully halogenated and which is optionally substituted withone to three C₁₋₃ alkyl groups, or an analog of such cycloalkyl groupwherein instead of one to three ring methylene groups there are groupsindependently selected from O, S, CHOH, >C═O, >C═S and NH;

(c) C₃₋₁₀ branched alkenyl which is optionally partially or fullyhalogenated, and which is optionally substituted with one to threegroups independently selected from C₁₋₅ branched or unbranched alkyl,phenyl, naphthyl or heteroaryl, with each such heteroaryl group beingindependently selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyland isothiazolyl, and each such phenyl, naphthyl or heteroaryl groupbeing substituted with 0 to 5 groups selected from halogen, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl,hydroxy, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, aminocarbonyl and mono- or di(C₁₋₃)alkylaminocarbonyl;

(d) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl andbicycloheptenyl, wherein such cycloalkenyl group is optionallysubstituted with one to three C₁₋₃ alkyl groups;

(e) cyano; and,

(f) an alkoxy carbonyl group selected from methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl;

R₂ is selected from the group consisting of the following, when B is acarbon atom or an amino nitrogen: hydrogen, C₁₋₆ branched or unbranchedalkyl which is optionally partially or fully halogenated, acetyl,benzoyl and phenylsulfonyl; R₃ is selected from the group consisting ofthe following, when D is a carbon atom or an amino nitrogen:

a) phenyl, naphthyl and heteroaryl (wherein said heteroaryl group isselected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl,quinazolinyl, purinyl and indazolyl), wherein such phenyl, naphthyl orheteroaryl group is optionally substituted with one to five groupsindependently selected from C₁₋₆ branched or unbranched alkyl, phenyl,naphthyl, heteroaryl selected from the group set forth immediatelyabove, C₁₋₆ branched or unbranched alkyl which is optionally partiallyor fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl,bicycloheptanyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl, halo, hydroxy,cyano, C₁₋₃ alkyloxy which is optionally partially or fully halogenated,phenyloxy, naphthyloxy, heteraryloxy wherein the heteroaryl moiety isselected from the group set forth above in this subparagraph, nitro,amino, mono- or di-(C₁₋₃) alkylamino, phenylamino, naphthylamino,heteroarylamino wherein the heteroaryl moiety is selected from the groupset forth above in this subparagraph, aminocarbonyl, a mono- ordi-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄ branched or unbranched alkyloxycarbonyl, C₁₋₅ alkylcarbonyl C₁₋₄ branched or unbranched alkyl, aminoC₁₋₅ alkyl, mono- or di-(C₁₋₃) alkylamino(C₁₋₅)alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl;

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl), and fused heteroaryl (selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,cyclohexanobenzimidazole, cyclopentanobenzoxazole,cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole,cyclopentanothiophene and cyclohexanothiophene), wherein the fused arylor fused heteroaryl ring is substituted with 0 to 3 groups independentlyselected from phenyl, naphthyl and heteroaryl (wherein each suchheteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyland isothiazolyl), C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, halo, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy,heteroaryloxy (wherein the heteroaryl moiety is selected from the groupset forth above in this subparagraph), nitro, amino, mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heteroarylamino(wherein the heteroaryl moiety is selected from the group set forthabove in this subparagraph), aminocarbonyl, a mono- or di-(C₁₋₃)alkylaminocarbonyl, C₁₋₄ branched or unbranched alkyl oxycarbonyl, C₁₋₅alkylcarbonyl C₁₋₄ branched or unbranched alkyl, amino C₁₋₅ alkyl, mono-or di-(C₁₋₃)alkylamino(C₁₋₅) alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl;

c) a cycloalkyl group selected from cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl,which cycloalkyl group is optionally partially or fully halogenated andwhich is optionally substituted with one to three C₁₋₃ alkyl groups;

d) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl andbicycloheptenyl, wherein such cycloalkenyl group is optionallysubstituted with one to three C₁₋₃ alkyl groups; and,

e) acetyl, benzoyl and phenylsulfonyl;

or R¹ and R₂ taken together may optionally form a fused phenyl orpyridinyl ring,

or R₂ and R₃ taken together may optionally form a fused phenyl orpyridinyl ring,

R₄ is selected from the following, when G is a carbon atom or an aminonitrogen: hydrogen and C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated;

R₅ is selected from the group consisting of:

a) phenyl, naphthyl and heteroaryl (wherein such heteroaryl is selectedfrom pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl,quinazolinyl, purinyl and indazolyl), wherein such phenyl, naphthyl orheteroaryl group optionally bears one to five groups selected fromphenyl, naphthyl and heteroaryl (wherein each such heteroaryl moiety isindependently selected from the group defined above in thissubparagraph), C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl,bicycloheptanyl, halo, cyano, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, phenyloxy, naphthyloxy, nitro, amino,mono- or di- (C₁₋₃) alkylamino, phenylamino, naphthylamino,aminocarbonyl, mono- or di-(C₁₋₃) alkylaminocarbonyl, amino(C₁₋₅)alkylor alkenyl, di-(C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl,phenylamino(C₁₋₃)alkyl or alkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl,phenylamido(C₁₋₃)alkyl or alkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl,phenyl(C₁₋₅)alkyl or alkenyl and naphthyl(C₁₋₅)alkyl or alkenyl;

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl), and fused heteroaryl (selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,cyclohexanobenzimidazole, cyclopentanobenzoxazole,cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole,cyclopentanothiophene and cyclohexanothiophene), wherein the fused arylor fused heteroaryl ring bears 0 to 3 groups selected from phenyl,naphthyl, heteroaryl (wherein such heteroaryl is selected frompyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl), C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, nitro, amino, mono- or di- (C₁₋₃)alkylamino, phenylamino, naphthylamino, aminocarbonyl, mono- ordi-(C₁₋₃) alkylaminocarbonyl, amino(C₁₋₅)alkyl or alkenyl,di-(C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl, phenylamino(C₁₋₃)alkyl oralkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamido(C₁₋₃)alkyl oralkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl, phenyl(C₁₋₅)alkyl oralkenyl and naphthyl(C₁₋₅)alkyl or alkenyl;

c) cycloalkyl selected from cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which cycloalkylgroup is optionally partially or fully halogenated and which isoptionally substituted with one to three C₁₋₃ alkyl groups;

d) cycloalkenyl selected from cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl andbicycloheptenyl, which cycloalkenyl group is optionally partially orfully halogenated and which is optionally substituted with one to threeC₁₋₃ alkyl groups; and

e) phenyl(C₁₋₅ branched or unbranched)alkyl, and naphthyl(C₁₋₅ branchedor unbranched)alkyl, wherein the phenyl or naphthyl ring is substitutedwith 0 to 5 groups selected from the group consisting of phenyl,naphthyl, heteroaryl (selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyland isothiazolyl), C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, halo, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy orheteroaryloxy (wherein the heteroaryl moiety is as defined above in thissubparagraph);

R₆ is hydrogen, cyano or C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated; and,

R₇ is hydrogen or C₁₋₆ branched or unbranched alkyl, which is optionallypartially or fully halogenated.

In a somewhat preferred generic aspect, the invention comprisescompounds of the above formula I, wherein:

the heterocyclic moiety

is selected from the group consisting of:

X is S, O or NR₆;

Y is N—H;

R₁ is selected from the group consisting of:

a) C₃₋₁₀ branched alkyl, which is optionally partially or fullyhalogenated, and optionally substituted with one to three phenyl,naphthyl or heteroaryl groups (each such heteroaryl group beingindependently selected from pyridinyl and thienyl), each such phenyl,naphthyl or heteroaryl group being substituted with 0 to 5 groupsselected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, C₃₋₈ cycloalkyl, C₅₋₈cycloalkenyl, hydroxy, cyano, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, aminocarbonyl anddi(C₁₋₃)alkylaminocarbonyl;

b) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which cycloalkyl group is optionallypartially or fully halogenated and which is optionally substituted withone to three C₁₋₃ alkyl groups, or an analog of such cycloalkyl groupwherein instead of one to three ring methylene groups there are groupsindependently selected from O, S, CHOH, >C═O, >C═S and NH;

c) C₃₋₁₀ branched alkenyl which is optionally partially or fullyhalogenated, and which is optionally substituted with one to threegroups independently selected from C₁₋₅ branched or unbranched alkyl,phenyl, naphthyl or heteroaryl, with each such heteroaryl group beingindependently selected from pyridinyl and thienyl and each such phenyl,naphthyl or heteroaryl group being substituted with 0 to 5 groupsselected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, hydroxy, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl;

d) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl andbicycloheptenyl, wherein such cycloalkenyl group is optionallysubstituted with one to three C₁₋₃ alkyl groups;

e) an alkoxy carbonyl group selected from methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl;

R₂ is selected from the group consisting of the following, when B is acarbon atom or an amino nitrogen: hydrogen, C₁₋₆ branched or unbranchedalkyl which is optionally partially or fully halogenated, benzoyl andphenylsulfonyl;

R₃ is selected from the group consisting of the following, when D is acarbon atom or an amino nitrogen:

a) phenyl, naphthyl and heteroaryl (wherein said heteroaryl group isselected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, faryl, isoxazolyl, isothiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl andbenzoxazolyl), wherein such phenyl, naphthyl or heteroaryl group isoptionally substituted with one to three groups independently selectedfrom C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, heteroarylselected from the group set forth immediately above, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C, alkyl,naphthyl C₁₋₅ alkyl, halo, hydroxy, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy,heteraryloxy wherein the heteroaryl moiety is selected from the groupset forth above in this subparagraph, nitro, amino, mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heteroarylamino whereinthe heteroaryl moiety is selected from the group set forth above in thissubparagraph, aminocarbonyl, a mono- or di-(C₁₋₃)alkyl aminocarbonyl,C₁₋₄ branched or unbranched alkyl oxycarbonyl, C₁₋₅ alkylcarbonyl C₁₋₄branched or unbranched alkyl, amino C₁₋₅ alkyl, mono- ordi-(C₁₋₃)alkylamino(C₁₋₅)alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl;

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl), and fused heteroaryl (selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanothiophene andcyclohexanothiophene), wherein the fused aryl or fused heteroaryl ringis substituted with 0 to 3 groups independently selected from phenyl,naphthyl and heteroaryl (wherein each such heteroaryl is selected frompyridinyl and thienyl), C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, halo, cyano, C₁₋₃ alkyloxywhich is optionally partially or fully halogenated, phenyloxy,naphthyloxy, heteroaryloxy (wherein the heteroaryl moiety is selectedfrom the group set forth above in this subparagraph), amino, mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heteroarylamino(wherein the heteroaryl moiety is selected from the group set forthabove in this subparagraph), aminocarbonyl, a mono- or di-(C₁₋₃)alkylaminocarbonyl, C₁₋₄ branched or unbranched alkyl oxycarbonyl, C₁₋₅alkylcarbonyl C₁₋₄ branched or unbranched alkyl, amino C₁₋₅ alkyl, mono-or di-(C₁₋₃)alkylamino(C₁₋₅)alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl;

c) a cycloalkyl group selected from cyclopentanyl, cyclohexanyl andcycloheptanyl, which cycloalkyl group is optionally partially or fullyhalogenated and which is optionally substituted with one to three C₁₋₃alkyl groups;

d) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl andcycloheptenyl, wherein such cycloalkenyl group is optionally substitutedwith one to three C₁₋₃ alkyl groups; and,

e) acetyl, benzoyl and phenylsulfonyl;

or R₁ and R₂ taken together may optionally form a fused phenyl orpyridinyl ring,

R₅ is selected from the group consisting of:

a) phenyl, naphthyl and heteroaryl (wherein such heteroaryl is selectedfrom pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thienyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl), wherein such phenyl, naphthyl orheteroaryl group optionally bears one to three groups selected fromphenyl, naphthyl and heteroaryl (wherein each such heteroaryl moiety isindependently selected from the group defined above in thissubparagraph), C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, halo, cyano, C₁₋₃ alkyloxy which is optionally partiallyor fully halogenated, phenyloxy, naphthyloxy, mono- or di- (C₁₋₃)alkylamino, phenylamino, naphthylamino, mono- or di-(C₁₋₃)alkylaminocarbonyl, amino(C₁₋₅)alkyl or alkenyl,di-(C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl, phenylamino(C₁₋₃)alkyl oralkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamido(C₁₋₃)alkyl oralkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl, phenyl(C₁₋₅)alkyl oralkenyl and naphthyl(C₁₋₅)alkyl or alkenyl;

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl), and fused heteroaryl (selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanothiophene andcyclohexanothiophene), wherein the fused aryl or fused heteroaryl ringbears 0 to 3 groups selected from phenyl, naphthyl, heteroaryl (whereinsuch heteroaryl is selected from pyridinyl and thienyl), C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, amino, mono- or di- (C₁₋₃)alkylamino, phenylamino, naphthylamino, aminocarbonyl, mono- ordi-(C₁₋₃) alkylaminocarbonyl, amino(C₁₋₅)alkyl or alkenyl,di-(C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl, phenylamino(C₁₋₃)alkyl oralkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamido(C₁₋₃)alkyl oralkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl, phenyl(C₁₋₅)alkyl oralkenyl and naphthyl(C₁₋₅)alkyl or alkenyl;

c) cycloalkyl selected from cyclopentanyl, cyclohexanyl andcycloheptanyl, which cycloalkyl group is optionally partially or fullyhalogenated and which is optionally substituted with one to three C₁₋₃alkyl groups;

d) cycloalkenyl selected from cyclopentenyl and cyclohexenyl, whichcycloalkenyl group is optionally partially or fully halogenated andwhich is optionally substituted with one to three C₁₋₃ alkyl groups; and

e) phenyl(C₁₋₅ branched or unbranched)alkyl, and naphthyl(C₁₋₅ branchedor unbranched)alkyl, wherein the phenyl or naphthyl ring is substitutedwith 0 to 5 groups selected from the group consisting of phenyl,naphthyl, heteroaryl (selected from pyridinyl and thienyl), C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, halo, cyano, C₁₋₃ alkyloxy which is optionally partially orfully halogenated, phenyloxy, naphthyloxy or heteroaryloxy (wherein theheteroaryl moiety is as defined above in this subparagraph);

R₆ is hydrogen, cyano or C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated.

In a penultimately preferred generic aspect, the invention providescompounds of the above formula I, wherein:

the heterocyclic moiety

is selected from the group consisting of:

X is S or O;

Y is N—H;

R₁ is selected from the group consisting of:

a) C₃₋₁₀ branched alkyl, which is optionally partially or fullyhalogenated, and optionally substituted with one to three phenyl,naphthyl or heteroaryl groups (each such heteroaryl group beingindependently selected from pyridinyl and thienyl), each such phenyl,naphthyl or heteroaryl group being substituted with 0 to 3 groupsselected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, C₃₋₈ cycloalkyl, hydroxy,cyano and C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated;

b) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which cycloalkyl group is optionallypartially or fully halogenated and which is optionally substituted withone to three C₁₋₃ alkyl groups, or an analog of such cycloalkyl groupwherein instead of one to three ring methylene groups there are groupsindependently selected from O, S, CHOH, >C═O, >C═S and NH;

c) C₃₋₁₀ branched alkenyl which is optionally partially or fullyhalogenated, and which is optionally substituted with one to threegroups independently selected from C₁₋₅ branched or unbranched alkyl,phenyl, naphthyl or heteroaryl, with each such heteroaryl group beingindependently selected from pyridinyl and thienyl and each such phenyl,naphthyl or heteroaryl group being substituted with 0 to 3 groupsselected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl, hydroxy, cyano, and C₁₋₃ alkyloxy which is optionallypartially or fully halogenated;

d) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl,bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group isoptionally substituted with one to three C₁₋₃ alkyl groups;

e) an alkoxy carbonyl group selected from methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl;

R₂ is selected from the group consisting of the following, when B is acarbon atom or an amino nitrogen: hydrogen, C₁₋₆ branched or unbranchedalkyl which is optionally partially or fully halogenated, acetyl,benzoyl and phenylsulfonyl;

R₃ is selected from the group consisting of the following, when D is acarbon atom or an amino nitrogen:

a) phenyl, naphthyl and heteroaryl (wherein said heteroaryl group isselected from pyridinyl, quinolinyl and isoquinolinyl), wherein suchphenyl, naphthyl or heteroaryl group is optionally substituted with oneto three groups independently selected from C₁₋₆ branched or unbranchedalkyl, phenyl, naphthyl, heteroaryl selected from the group set forthimmediately above, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, phenyl C₁₋₅ alkyl, halo, hydroxy, cyano, C₁₋₃ alkyloxywhich is optionally partially or fully halogenated, phenyloxy,naphthyloxy, heteraryloxy wherein the heteroaryl moiety is selected fromthe group set forth above in this subparagraph, mono- or di-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heteroarylamino wherein theheteroaryl moiety is selected from the group set forth above in thissubparagraph, aminocarbonyl, a mono- or di-(C₁₋₃)alkyl aminocarbonyl,C₁₋₅ alkylcarbonyl C₁₋₄ branched or unbranched alkyl, amino C₁₋₅ alkyland mono- or di-(C₁₋₃)alkylamino(C₁₋₅)alkyl;

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl and tetrahydronaphthyl), and fused heteroaryl (selectedfrom cyclopentenopyridine, cyclohexanopyridine, cyclopentanothiopheneand cyclohexanothiophene), wherein the fused aryl or fused heteroarylring is substituted with 0 to 3 groups independently selected fromphenyl, naphthyl and heteroaryl (wherein each such heteroaryl isselected from pyridinyl and thienyl), C₁₋₆ branched or unbranched alkylwhich is optionally partially or fully halogenated, halo, cyano, C₁₋₃alkyloxy which is optionally partially or fully halogenated, phenyloxy,naphthyloxy, heteroaryloxy (wherein the heteroaryl moiety is selectedfrom the group set forth above in this subparagraph), mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heteroarylamino(wherein the heteroaryl moiety is selected from the group set forthabove in this subparagraph), aminocarbonyl, a mono- or di-(C₁₋₃)alkylaminocarbonyl, amino C₁₋₅ alkyl and mono- ordi-(C₁₋₃)alkylamino(C₁₋₅)alkyl;

c) a cycloalkyl group selected from cyclopentanyl, cyclohexanyl andcycloheptanyl, which cycloalkyl group is optionally partially or fullyhalogenated and which is optionally substituted with one to three C₁₋₃alkyl groups;

d) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl andcycloheptenyl, wherein such cycloalkenyl group is optionally substitutedwith one to three C₁₋₃ alkyl groups;

e) acetyl, benzoyl and phenylsulfonyl; and,

or R₁ and R₂ taken together may optionally form a fused phenyl orpyridinyl ring,

R₅ is selected from the group consisting of:

a) phenyl, naphthyl and heteroaryl (wherein such heteroaryl is selectedfrom pyridinyl, thienyl, quinolinyl, isoquinolinyl and indolyl), whereinsuch phenyl, naphthyl or heteroaryl group optionally bears one to threegroups selected from phenyl, naphthyl and heteroaryl (wherein each suchheteroaryl moiety is independently selected from the group defined abovein this subparagraph), C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, halo, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy,,phenylamino, naphthylamino phenylamino(C₁₋₃)alkyl or alkenyl,naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamido(C₁₋₃)alkyl or alkenyl,naphthylamido(C₁₋₃)alkyl or alkenyl, heteroarylamido(C₁₋₃)alkyl oralkenyl (wherein the heteroaryl moiety is as defined above in thissubparagraph);

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl), and fused heteroaryl (selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanothiophene andcyclohexanothiophene), wherein the fused aryl or fused heteroaryl ringbears 0 to 3 groups selected from phenyl, naphthyl, heteroaryl (whereinsuch heteroaryl is selected from pyridinyl and thienyl), C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, , phenylamino, naphthylamino,phenylamino(C₁₋₃)alkyl or alkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl,phenylamido(C₁₋₃)alkyl or alkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl,heteroarylamido(C₁₋₃)alkyl or alkenyl (wherein the heteroaryl moiety isas defined above in this subparagraph); and,

c) phenyl(C₁₋₅ branched or unbranched)alkyl, and naphthyl(C₁₋₅ branchedor unbranched)alkyl, wherein the phenyl or naphthyl ring is substitutedwith 0 to 3 groups selected from the group consisting of phenyl,naphthyl, heteroaryl (selected from pyridinyl and thienyl), C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, halo, cyano, C₁₋₃ alkyloxy which is optionally partially orfully halogenated, phenyloxy, naphthyloxy or heteroaryloxy (wherein theheteroaryl moiety is as defined above in this subparagraph).

In an ultimately preferred generic aspect, the invention providescompounds of the formula I, wherein:

the heterocyclic moiety

is selected from the group consisting of:

X is S or O;

Y is N—H;

R₁ is selected from the group consisting of:

a) C₃₋₇ branched alkyl, which is optionally partially or fullyhalogenated, and optionally substituted with one to three phenyl orheteroaryl groups (each such heteroaryl group being independentlyselected from pyridinyl and thienyl), each such phenyl or heteroarylgroup being substituted with 0 to 3 groups selected from halogen, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, C₃₋₈ cycloalkyl and C₁₋₃ alkyloxy which is optionallypartially or fully halogenated;

b) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which cycloalkyl group is optionallypartially or fully halogenated and which is optionally substituted withone to three C₁₋₃ alkyl groups;

c) C₃₋₇ branched alkenyl which is optionally partially or fullyhalogenated, and which is optionally substituted with one to threegroups independently selected from C₁₋₅ branched or unbranched alkyl,phenyl or heteroaryl, with each such heteroaryl group beingindependently selected from pyridinyl and thienyl and each such phenylor heteroaryl group being substituted with 0 to 3 groups selected fromhalogen, C,-₆ branched or unbranched alkyl which is optionally partiallyor fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl and C₁₋₃alkyloxy which is optionally partially or fully halogenated;

R₃ is selected from the group consisting of the following, when D is acarbon atom or an amino nitrogen:

a) phenyl, naphthyl and heteroaryl (wherein said heteroaryl group isselected from pyridinyl, quinolinyl and isoquinolinyl), wherein suchphenyl, naphthyl or heteroaryl group is optionally substituted with oneto three groups independently selected from C₁₋₆ branched or unbranchedalkyl, phenyl, naphthyl, heteroaryl selected from the group set forthimmediately above, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, halo, hydroxy, cyano, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, phenyloxy, heteraryloxy wherein theheteroaryl moiety is selected from the group set forth above in thissubparagraph, mono- or di-(C₁₋₃)alkylamino, phenylamino, heteroarylaminowherein the heteroaryl moiety is selected from the group set forth abovein this subparagraph, aminocarbonyl, a mono- or di-(C₁₋₃)alkylaminocarbonyl and mono- or di-(C₁₋₃)alkylamino(C₁₋₅)alkyl;

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl and tetrahydronaphthyl), and fused heteroaryl (selectedfrom cyclopentenopyridine, cyclohexanopyridine, cyclopentanothiopheneand cyclohexanothiophene), wherein the fused aryl or fused heteroarylring is substituted with 0 to 3 groups independently selected fromphenyl and heteroaryl (wherein each such heteroaryl is selected frompyridinyl and thienyl), C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, halo, cyano, C₁₋₃ alkyloxywhich is optionally partially or fully halogenated, phenyloxy,heteroaryloxy (wherein the heteroaryl moiety is selected from the groupset forth above in this subparagraph), mono- or di-(C₁₋₃)alkylamino,phenylamino, heteroarylamino (wherein the heteroaryl moiety is selectedfrom the group set forth above in this subparagraph), aminocarbonyl, amono- or di-(C₁₋₃)alkyl aminocarbonyl and mono- ordi-(C₁₋₃)alkylamino(C₁₋₅)alkyl;

c) a cycloalkyl group selected from cyclopentanyl, cyclohexanyl andcycloheptanyl, which cycloalkyl group is optionally partially or fullyhalogenated and which is optionally substituted with one to three C₁₋₃alkyl groups;

d) acetyl, benzoyl and phenylsulfonyl; and,

R₅ is selected from the group consisting of:

a) phenyl, naphthyl and heteroaryl (wherein such heteroaryl is selectedfrom pyridinyl, thienyl, quinolinyl and isoquinolinyl), wherein suchphenyl, naphthyl or heteroaryl group optionally bears one to threegroups selected from phenyl and heteroaryl (wherein each such heteroarylmoiety is independently selected from the group defined above in thissubparagraph), C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, halo, cyano, C₁₋₃ alkyloxy which is optionally partiallyor fully halogenated, phenyloxy, phenylamino;

b) fused aryl (selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl), and fused heteroaryl (selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanothiophene andcyclohexanothiophene), wherein the fused aryl or fused heteroaryl ringbears 0 to 3 groups selected from phenyl, C₁₋₆ branched or unbranchedalkyl which is optionally partially or fully halogenated, halo, cyano,C₁₋₃ alkyloxy which is optionally partially or fully halogenated,phenyloxy and phenylamino; and,

c) phenyl(C₁₋₅ branched or unbranched)alkyl, and naphthyl(C₁₋₅ branchedor unbranched)alkyl, wherein the phenyl or naphthyl ring is substitutedwith 0 to 3 groups selected from the group consisting of phenyl, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, halo, cyano, C₁₋₃ alkyloxy which is optionally partially orfully halogenated and phenyloxy.

Specifically preferred compounds in accordance with the invention arethose selected from the group consisting of:

1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-(4-chlorophenyl)urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-methoxynaphthalen-1-yl)urea;

1-(5-tert-Butyl-2-(3,4-dimethylphenyl)-2H-pyrazol-3-yl)-3-(4-fluorophenyl)urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(2-fluorophenyl)urea; and

1-[5-tert-Butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-(4-cyanonaphthalen-1-yl)urea.

Any compounds of this invention containing one or more asymmetric carbonatoms may occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention. Each stereogenic carbon may be in the R or S configuration,or a combination of configurations.

Some of the compounds of formula I can exist in more than one tautomericform. The invention includes all such tautomers.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula 1. “A pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester of a compound ofthis invention, or any other compound which, upon administration to apatient, is capable of providing (directly or indirectly) a compound ofthis invention, a pharmacologically active metabolite orpharmacologically active residue thereof.

Pharmaceutically acceptable salts of the compounds of the inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N-(C₁-C₄ alkyl)₄ ⁺salts.

In addition, the invention include prodrugs of the compounds ofcompounds of the formula I. Prodrugs include those compounds that, uponsimple chemical transformation, are modified to produce a compound offormula I. Simple chemical transformations include hydrolysis, oxidationand reduction. Specifically, when a prodrug of this invention isadministered to a patient, the prodrug may be transformed into acompound of formula I, thereby imparting the desired pharmacologicaleffect.

GENERAL SYNTHETIC METHODS

The compounds of the invention may be prepared by Method A or B asillustrated in Scheme 1.

In Method A, a mixture of an aminoheterocycle of formula II and anarylisocyanate of formula III is dissolved in a non-protic, anhydroussolvent such as THF, ether, toluene, dioxane or ethyl acetate. Thepreferred solvent is THF. The mixture is stirred at between 0-45° C.,preferably at 25° C., for 2-24 hr, and the volatiles are removed.Purification of the residue by recrystallization or silica gelchromatography, using hexanes and ethyl acetate as eluents, provides theproduct of formula I.

In Method B, an aminoheterocycle of formula II is dissolved in ahalogenated solvent, such as methylene chloride, chloroform ordichloroethane. The preferred solvent is methylene chloride. The mixtureis diluted with aqueous alkali, such as sodium bicarbonate or potassiumcarbonate, cooled in an ice bath and phosgene is added. The mixture isvigorously stirred for 5-30 min, with 10 min being preferable. Theorganic layer is dried, with agents such as MgSO₄ or Na₂SO₄, and thevolatiles removed to provide the corresponding isocyanate of formula II.The isocyanate and arylamine IV are mixed in a non-protic, anhydroussolvent such as THF, ether, toluene, dioxane, methylene chloride orethyl acetate. The preferred solvent is THF. The mixture is stirred atbetween 0-45° C., preferably at 25° C., for 2-24 hr, and the volatilesare removed. Purification of the residue by recrystallization or silicagel chromatography, using hexanes and ethyl acetate as eluents, providesthe product of formula I.

The method used to produce an aminoheterocycle of formula II will dependon the nature of the desired heterocycle. In general, intermediates offormula II can be made by methods known to those skilled in the art.Some general methods are illustrated in the schemes below. Amines andisocyanates bearing R₅ used in Method A or B respectively are availablecommercially or easily prepared by methods known to those skilled in theart.

Desired aminopyrazoles of formula XII can be prepared as described inScheme II. A hydrazine of formula VII, bearing substituent R₃, may beprepared by Method C or D. In Method C, an aryl bromide of formula V isdissolved in a non-protic, inert solvent, such as THF, 1,4-dioxane ordiethyl ether, and cooled to low temperature under an inert atmosphere.The preferred temperature for the solution is −77° C. A strong basedissolved in a non-protic, inert solvent, such as hexanes, THF or ether,is added dropwise while maintaing a reaction temperature below 0° C. andpreferrably below −60° C. The preferred bases are alkyl lithium reagentsand the most preferred is secbutyl lithium. After the addition of thebase, the reaction mixture is stirred for a period of time betweenthirty and ninety minutes or until all the starting aryl bromide hasbeen consumed. An excess of dialkyl azodicarboxylate is added whilemaintaining a reaction temperature below 0° C. and preferrably below−60° C. The preferred dialkyl azodicarboxylate is di-tert-butylazodicarboxylate. The reaction is stirred at cold temperatures andwarmed to room temperature after 0.5 hr to 2 hr. The reaction isquenched with the addition of water and the product extracted into anon-protic solvent, such as ethyl acetate, diethyl ether or chloroform.The organic layers are dried with agents such as MgSO₄ or Na₂SO₄ and thevolatiles removed. The residue is dissolved in protic solvents, such asmethanol or iso-propanol, cooled, preferably to 0-5° C. and treated withacid. Preferred acids are hydrochloric, hydrobromic, sulfuric andtrifluoroacetic. The most preferred is hydrochloric in gaseous form.After the addition of excess acid the mixture is heated at the refluxtemperature of the solvent until all starting material has beenconsumed. After cooling the product aryl-hydrazine of formula VII saltis filtered and dried.

In Method D, an aryl amine bearing R₃ of formula VI is dissloved in aconcentrated aqueous acid such as hydrochloric, hydrobromic and sulfuricand cooled to ice bath temperatures. The most preferred acid ishydrochloric with concentrations between 3-8N with the most preferredconcentration of 6N. A nitrosating reagent in water is added dropwisewhile maintaining a cold temperature. The preferred temperature is 0-5°C. The preferred reagent is sodium nitrite. The reaction is stirredbetween 10 -90 min and a reducing agent is added while maintaing coldtemperatures. The preferred temperature is 0-5° C. Reducing agentsinclude zinc, iron, samarium iodide and tin(II) chlroride. The mostpreferred agent is tin(II) chlroride dissolved in aqueous hydrochloridewith a concentration of 3-8 N with a most preferred concentration of 6N.The reaction is stirred between 0.5-3 hr and quenched with alkali to apH between 12-14. Alkali reagents include sodium hydroxide, potassiumhydroxide, lithium hydroxide and calcium hydroxide. The most preferredalkali reagent is potassium hydroxide. The aqueous solution is extractedwith a non-protic organic solvent, such as diethyl ether, chloroform,ethyl acetate and methylene chloride. The organic layers are dried withagents such as MgSO₄ and Na₂SO₄ and the volatiles removed to provide thearyl-hydrazine (VII) which can be carried forward without furtherpurification.

A β-ketonitrile bearing R₁ (XI) may be prepared by Method E or F. InMethod E, a metal hydride, such as sodium hydride, potassium hydride orlithium hydride, is suspended in an anhydrous, inert, non-proticsolvent, such as diethyl ether, THF and dioxane, at temperatures between35-85° C. The most preferred metal hydride is sodium hydride and themost preferred solvent is THF at a temperature of 75° C. An alkyl ester,preferably a methyl ester (VIII), and acetonitrile is dissolved in ananhydrous, inert, non-protic solvent, such as diethyl ether, THF ordioxane and added dropwise to the metal hydride suspension. Thepreferred solvent is THF. The mixture is kept at elevated temperaturesbetween 3-24 hours, cooled to room temperature and diluted with anon-protic solvent and aqueous acid. The organic layer is washed withwater and brine, dried, with agents such as MgSO₄ and Na₂SO₄, and thevolatiles removed to provide the β-ketonitrile (XI) which could be usedwithout further purification.

Alternatively, following Method F, a solution of a strong base, such asalkyl lithium reagents and metal amide reagents, such as n-butyllithium, sec-butyl lithium, methyl lithium and lithium diisopropylamide,in an anhydrous, inert, non-protic solvent, such as diethyl ether, THFand dioxane, is cooled below 0° C. The preferred base is n-butyllithium, the preferred solvent is THF and the preferred temperature is−77° C. A solution of cyanoacetic acid (IX) in an anhydrous, inert,non-protic solvent, such as diethyl ether, THF and dioxane, and mostpreferrably THF, is added dropwise while maintaining a reactiontemperature below 0° C. and preferrably at −77° C. The reaction isstirred between 10-45 min while warming to 0° C. The solution of thedianion of cyanoacetic is cooled to temperatures below −25° C. andpreferrably at −77° C. An alkyl acid chloride (X) dissolved in ananhydrous, inert, non-protic solvent, such as diethyl ether, THF anddioxane, and most preferrably THF, is added. The reaction mixture iswarmed to 0° C. betweeen 10-30 min. and quenched with aqueous acid. Theproduct is extracted with an organic solvent, such as chloroform, ethylacetate, ether and methylene chloride. The combined organic extracts aredried, with agents such as MgSO₄ and Na₂SO₄, and the volatiles removedto provide the β-ketonitrile (XI) which could be used without furtherpurification.

The desired aminopyrazole (XII) may then be prepared by Method G or H. IMethod G, aryl hydrazine VII and β-ketonitrile XI are mixed in anorganic solvent, such as toluene, ethanol, iso-propanol or t-butanol.The preferred solvent is ethanol. An acid, such as hydrochloric acid,p-toluene sulfonic acid, sulfuric acid, is added, The preferred acid isconcentrated hydrochloric acid. The mixture is heated to temperaturesbetween 50-100° C., preferrably at 80° C., for 10-24 hr and cooled toroom. The mixture is diluted with non-protic organic solvent, such asethyl acetate, ether, chloroform and methylene chloride, and washed withaqueous alkali, such as sodium bicarbonate and potassium carbonate. Theorganic layer is dried, with agents such as MgSO₄ and Na₂SO₄, and thevolatiles removed to provide a residue which is purified byrecrystallization or silica gel chromatography using hexanes and ethylacetate as eluents. The product-rich fractions are collected and thevolatiles removed to provide the desired amonopyrazole (XII).

Alternatively, using Method H, aryl hydrazine VII and β-ketonitrile XIare mixed in an organic solvent, such as toluene, ethanol, iso-propanoland t-butanol. The preferred solvent is toluene. The mixture is heatedat reflux temperatures for 3-24 hrs with azeotropic removal of water andworked up as described above providing the aminopyrazole XII.

A general synthesis for desired aminothiophenes is illustrated in SchemeIII, Method I.

A mixture of 1-aryl-5-alkyl-butane-1,4-dione (XIII) and a sulfatingreagent, such as Lawesson's reagent and phosphorous (V) sulfide, andpreferrably Lawesson's reagent, is dissolved in a non-protic, anhydroussolvent, such as toluene, THF and dioxane. The preferred solvent istoluene. The mixture is heated at elevated temperatures and preferablyat a solvent-refluxing temperature for 1-10 hr. The volatiles areremoved and the residue is purified by silica gel chromatography usinghexanes and ethyl acetate as eluent. The product-rich fractions arecollected and the volatiles removed to provide the substituted thiopheneXIV.

A mixture of substituted thiophene XIV is dissolved in a solvent such asacetic anhydride or acetic acid. The preferred solvent is aceticanhydride. The mixture is cooled to 0-30° C. and preferrably to −10° C.A solution of concentrated nitric acid in a solvent such as aceticanhydride or acetic acid, with the preferred solvent being aceticanhydride and cooled to 0-30° C. and preferrably to −10° C. is added.The mixture is stirred between 10-120 min, poured onto ice and extractedwith a non-protic solvent such as diethyl ether, chloroform, ethylacetate or methylene chloride. The organic extracts are washed withaqueous alkali, dried with agents such as MgSO₄ and Na₂SO₄ and thevolatiles removed. The residue is purified by silica gel chromatographyusing hexanes and ethyl acetate as eluents. The product-rich fractionsare collected and the volatiles removed to provide the2-aryl-5-alkyl-3-nitrothiophene. The 2-aryl-5-alkyl-3-nitrothiophene isreduced by metals, such as iron, tin and zinc or catalytichydrogenation. The preferred reduction occurs with iron in acetic acidat temperatures between 50-110° C. and preferrably at 100° C. for 5-30min. After cooling to room temperature the reaction is diluted withwater, neutralized with alkali, such as sodium hydroxide, potassiumhydroxide, potassium carbonate or sodium bicarbonate, and extracted witha non-protic solvent such as diethyl ether, ethyl acetate or methylenechloride. The organic extracts are dried with agents such as MgSO₄ andNa₂SO₄ and the volatiles removed to provide the desired aminothiopheneXV.

Other desired aminoheterocycles can be prepared by methods known in theart and described in the literature. The examples that follow areillustrative and, as recognized by one skilled in the art, particularreagents or conditions could be modified as needed for individualcompounds. Intermediates used in the schemes below are eithercommercially available or easily prepared from commercially availablematerials by those skilled in the art.

Scheme IV outlines a general scheme for desired aminofurans as describedby Stevenson et al. (J. Am. Chem. Soc., 1937, 59, 2525). An ethylaroylacetate (XVI) is dissolved in a non-protic solvent, such as etherorTHF, and treated with a strong base, such as sodium, sodium ethoxideor sodium hydride, and the anion is reacted with a bromomethylalkylketone (XVII) at low temperatures, such as 0° C. After stirring thereaction until no starting material remains, it is poured onto coldwater and extracted with a non-protic solvent. The combined extracts aredried with agents such as MgSO₄ or Na₂SO₄. The diketo-ester (XVIII) maybe carried forward without further purification or purified bydistillation or silica gel chromatography. The diketo-ester in a proticsolvent, such as ethanol, is heated in the presence of a mineral acid,such as sulfuric and hydrochloric, for 5-10 hr. and extracted with anon-protic solvent. The combined extracts are dried with agents such asMgSO₄ or Na₂SO₄. The furan-ester (XIX) may be carried forward withoutfurther purification or purified by distillation or silica gelchromatography. The furan-ester in a protic solvent, such as ethanol, istreated with hydrazine hydrate and the mixture heated for 2-5 days. Thehydrazide is isloated as above and treated with hot formic acid and theresulting furan-amine (XX) purified by distillation or silica gelchromatography.

The synthesis of substituted 4-aminooxazoles may be achieved analogousto a procedure described by Lakhan et al. (J. Het. Chem., 1988, 25,1413) and illustrated in Scheme V. A mixture of aroyl cyanide (XXI),aldeyde (XXII) and anhydrous ammonium acetate in acetic acid is heatedat 100-110° C. for 3-6 hr, cooled to room temperature and quenched withwater. Extraction by a non-protic solvent provides the product XXIIIwhich can be carried forward without further purification or purified byrecrystallization or silica gel chromatography.

The synthesis of substituted 3-aminopyrroles (XXVII) may be achieved ina manner analogous to Aiello et al., J. Chem. Soc. Perkins Trans. I,1981, 1. This is outlined in Scheme VI. A mixture of aryldioxoalkane(XXIV) and amine (XXV) in acetic acid is heated at 100-110° C. for 3-6hr and worked up in the usual manner. The product (XXVI) in acetic acidis treated with a nitrating agent, such as nitric acid and potassiumnitrate in concentrated sulfuric acid. The mixture is poured onto coldwater and extracted with a non-protic solvent. The combined extracts aredried with agents such as MgSO₄ and Na₂SO₄. Removal of the volatilesprovides the nitro-pyrrole which which may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography. The nitro-pyrrole is reduced to the amine with iron inacetic acid or by catalytic hydrogenation using palladium on activatedcarbon. The aminopyrrole (XXVII) may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography.

In an analogous fashion, a mixture of amine XXVIII and3-aryl-2,5-dioxoalkane (XXIX) in acetic acid is heated between 80-110°C. for 2-24 hr. The reaction is diluted with water and extracted with anorganic solvent. The combined extracts are dried with agents such asMgSO₄ or Na₂SO₄ and the volatiles removed. The resulting pyrrole istreated with a nitrating agent and subsequently reduced to XXX asdescribed above. The product may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography. This process is illustrated in Scheme VII.

Substituted 5-aminothiazoles (XXXIV) may be prepared in a manneranalogous to Gerwald et al., J. Prakt. Chem. 1973, 315, 539. Asillustrated in Scheme VIII, to a mixture of aminocyanide XXXI, aldehydeXXXII and sulfur in an anhydrous solvent, such as ethanol and methanol,is added dropwise a base, such as triethylamine. The mixture is heatedat 50° C. for 1-3 hr. The mixture is cooled and the excess sulfurremoved. Acetic acid is added to neutralize the mixture and the solidcollected. The imine XXXIII is treated with acid, such as hydrchloricand toluenesulfonic acid, in water and an organic solvent. After thestaring material is consumed the reaction is worked up and the productXXXIV may be carried forward without further purification or purified byrecrystallization or silica gel chromatography.

A synthesis of substituted 2-aminothiophenes (XXXVI), analogous to aprocedure described by Gewald et al. (J. Prakt. Chem., 1973, 315, 539)is illustrated in Scheme IX. A mixture of disubstitutedthiophene-3-carboxylic acid (XXXV) in a protic solvent such as aceticacid, at a temperature of 0-50° C. is treated with a nitrating agent,such as nitric acid or potassium nitrate in concentrated sulfuric acid.After the starting material has been consumed the reaction is pouredonto ice and the product extracted with a non-protic solvent. Thecombined extracts are dried with agents such as MgSO₄ and Na₂SO₄ and thevolatiles removed. The nitrothiophene is reduced to the amine with ironin acetic acid or by catalytic hydrogenation using palladium onactivated carbon. The amino-thiophene may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography.

1,5-Disubstituted-3-aminopyrazoles (XXXIX) may be prepared as shown inScheme X, in a fashion analogous to the procedure described by Ege etal. (J. Het. Chem., 1982, 19, 1267). Potassium is added to anhydroust-butanol and the mixture cooled to 5° C. Hydrazine XXXVII is added,followed by cyanodibromoalkane XXXVIII. The mixture is heated atrefluxing temperatures for 3-10 hr. The mixture is cooled to roomtemperature and poured onto ice water. The product is extracted with anorganic solvent. The combined extracts are dried with agents such asMgSO₄ or Na₂SO₄ and the volatiles removed. The product XXXIX may becarried forward without further purification or purified byrecrystallization or silica gel chromatography.

The synthesis of 2-amino-3,5-disubstituted thiophenes shown in SchemeXI, is done in a fashion analogous to Knoll et al., J. Prakt. Chem.,1985, 327, 463. A mixture of substitutedN-(3-aminothioacryloyl)-formamidine (XL) and substituted bromide (XLI)in a protic solvent, such as methanol or ethanol, is heated, preferablyat a reflux temperature, for 5-30 min and cooled below room temperature.The product thiophene-imine is filtered and dried. The thiophene-imineXLII is converted to the thiopheneamine (XLIII) by treatment withaqueous acid.

The synthesis of 1,4-disubstituted-2-aminopyrroles (XLVII) may beaccomplished in a manner analogous to Brodrick et al. (J. Chem. Soc.Perkin Trans. I, 1975, 1910), and as illustrated in Scheme XII. Thepotassium salt of formylnitrile XLIV in water is treated with amine XLVand acetic acid and the mixture heated at 50-90° C. for 5-30 min. Theaminonitrile XLVI is collected by filtration upon cooling and then isstirred at room temperature with a base such as ethanolic potassiumethoxide for 2-5 hr and the volatiles removed. The residue is dilutedwith water and extracted with an organic solvent. The combined extractsare dried with agents such as MgSO₄ and Na₂SO₄ and the volatilesremoved. The product (XLVII) may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography.

The preparation of 1,2-disubstituted-4-aminoimidazoles by reduction ofthe corresponding nitro compound, for example with iron in acetic acidor catalytic hydrogenation may be accomplished as described by Al-Shaaret al. (J. Chem. Soc. Perkin Trans. I, 1992, 2779) and illustrated inScheme XIII.

2,4-Disubstituted 5-aminooxazoles (LIV) may be prepared in a manneranalogous to the procedure described by Poupaert et al. (Synthesis,1972, 622) and illustrated in Scheme XIV. Acid chloride L is added to acold mixture of 2-aminonitrile LI and a base such as triethylamine in anon-protic solvent, such as TUF, benzene, toluene or ether. Thepreferred temperature is 0° C. The mixture is stirred for 12-24 hr andwashed with water. The volatiles are removed and the product LII treatedwith ethylmercaptan and dry hydrogen chloride in dry methylene chloridefor 5-30 min. The solid 5-imino-1,3-oxazole hydrochloride (LIII) iscollected by filtration, dissolved in dry pyridine and the solutionsaturated with hydrogen sulfide during 4 hr at 0° C. The mixture isdiluted with an organic solvent and washed with water and dried. Removalof the volatiles provides the 5-amino-1,3-oxazole product (LIV) whichmay be carried forward without further purification or be purified bysilica gel chromatography.

The synthesis of 1,4-disubstituted-2-aminopyrazoles may be accomplishedas illustrated in Scheme XV and described in Lancini et al., J. Het.Chem., 1966, 3, 152. To a mixture of substituted aminoketone (LV) andcyanamide in water and acetic acid was added aqueous sodium hydroxideuntil pH 4.5 is reached. The mixture is heated at 50-90° C. for 1-5 hr,cooled and basicified with ammonium hydroxide. The product LVI iscollected by filtration and dried.

As in the cases described above, the synthesis of many otheraminoheterocycles useful as intermediates may be accomplished by methodssimilar to those described in the literature or known to those skilledin the art. Several additional examples are illustrated in Scheme XVI.2,5-Disubstituted-3-aminotriazoles (LVII) have been described byPlenkiewicz et al. (Bull. Chem. Soc. Belg. 1987, 96, 675).1,3-Disubstituted-4-aminopyrazoles (LVIII) have been described byGuarneri et al. (Gazz. Chim. Ital. 1968, 98, 569). Damany et al.(Tetrahedron, 1976, 32, 2421) describe a 2-amino-3-substitutedbenzothiophene (LIX). A 3-aminoindole (LX) is described by Foresti etal.. (Gazz. Chim. Ital., 1975, 125, 151). Bristow et al. (J. Chem. Soc.,1954, 616) describe an imidazo[1,2-a]pyridin-2-yl amine (LXI).

METHODS OF THERAPEUTIC USE

The compounds of the invention effectively block inflammatory cytokineproduction from cells. The inhibition of cytokine production is anattractive means for preventing and treating a variety of disordersassociated with excess cytokine production, e.g., diseases andpathological conditions involving inflammation. Thus, the compounds ofthe invention are useful for the treatment of such conditions. Theseencompass chronic inflammatory diseases including, but not limited to,rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome,Crohn's disease, ulcerative colitis, psoriasis, graft versus hostdisease, systemic lupus erythematosus and insulin-dependent diabetesmellitus. The compounds of the invention can also be used to treat otherdisorders associated with the activity of elevated levels ofproinflammatory cytokines such as responses to various infectious agentsand a number of diseases of autoimmunity such as toxic shock syndrome,osteoarthritis, diabetes and inflammatory bowel diseases unrelated tothose listed above are discussed above, in the Background of theInvention.

For therapeutic use, the compounds of the invention may be administeredin any conventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutic compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 15%, but morepreferably at least about 20%, of a compound of formula (I) (w/w) or acombination thereof.

Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

As mentioned above, dosage forms of the compounds of this inventioninclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 10-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patients generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

SYNTHETIC EXAMPLES EXAMPLE 1

Synthesis of1-(5-tert-butyl-2-phenylthiophen-3-yl)-3-(4-chlorophenyl)urea

A mixture of 1-phenyl,5,5-dimethylhexane-1,5-dione (1, 1.18 gm) andLawesson's reagent (2.62 gm) in 25 mL toluene was heated at reflux for 2hours, cooled to room temperature and most of the volatiles were removedunder a stream of nitrogen. The residue was purified by flashchromatography using 50% ether in hexanes as the eluent. Concentrationin vacuo of the product-rich fractions provided thiophene 2. To 2 (0.81gm) in 5 mL acetic anhydride at −10° C. was added a cold (−10° C.)solution of nitric acid (0.24 mL, d=1.49) in 2 mL acetic anhydride. Themixture was stirred 45 minutes, poured onto ice and extracted withether. The combined organic extracts were washed with water, saturatedNaHCO₃, brine and dried (MgSO₄) and the volatiles removed in vacuo.Purification of the residue with flash chromatography using 5% ethylacetate in hexanes as the eluent provided nitrothiophene 3. A mixture of3 (0.67 gm) and iron powder (1.4 gm) in 10 mL acetic acid was heated at100° C. for 10 minutes, cooled to room temperature, diluted with water,basicified with solid potassium carbonate and extracted with ethylacetate. The combined extracts were washed with brine and dried (MgSO₄).Removal of the volatiles in vacuo provided aminothiophene 4. A mixtureof 4 (0.13 gm) and 4-chlorophenyl isocyanate (5, 82 mg) in 2 mLanhydrous THF was stirred at room temperature overnight and thevolatiles removed in vacuo. Purification of the residue by flashchromatography using 11% ethyl acetate in hexanes as the eluent andconcentration of the product rich-fraction in vacuo provided urea 6.

EXAMPEL 2

Synthesis of1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-(indan-2-yl)urea

A solution of phenylhydrazine (7, 10.9 gm) and4,4-dimethyl-3-oxopentanenitrile (8, 10.2 gm) in 25 mL of toluene washeated at reflux with azeotropic removal of water. After 4 hours thevolatiles were removed in vacuo and the residue purified by flash silicagel chromatography using 17% ethyl acetate in hexanes as the eluent.Concentration in vacuo of the product-rich fractions provided pyrazole9. A mixture of 9 (0.52 gm) and phosgene (2.5 mL of a 1.9 M toluenesolution) in 25 mL methylene chloride and 25 mL of aqueous saturatedsodium bicarbonate was vigorously stirred for 10 minutes in an ice bathand the aqueous layer extracted with methylene chloride. The combinedorganic layers were dried (magnesium sulfate) and the volatiles removedin vacuo. A mixture of the isocyanate (195 mg) and 2-aminoindan (10, 142mg) in 5 mL methylene chloride was stirred at room temperatureovernight. Removal of the volatiles in vacuo provide a residue which wascrystallized with ethyl acetate and hexanes and furnished urea 11 as awhite solid.

Example 3

Synthesis of 1-(1-phenyl-1H-benzoimidazol-2-yl)-3-(4-chlorophenyl)urea

A mixture of 2-amino-1-phenylbenzimidazole (12) and 4-chlorophenylisocyanate (5) was stirred at room temperature in methylene chlorideovernight. Removal of the volatiles in vacuo provide a residue which waspurified by recrystallization in ethyl acetate and hexanes to affordurea 13.

Using methods analogous to those described above, the compounds of theinvention described in the following Table 1 were either prepared (thosecompounds for which melting points are given) or could be prepared(those compounds for which no melting points are given).

TABLE 1

Ex. No. Het R₁ R₃ R₅ X m.p. ° C. 4 A t-butyl 4-methylphenyl 2,4- O230.5-231   dichlorophenyl 5 A 1-methylcyclo- 2-methyl- 5-fluoroindan- Ohexan-1-yl pyridin-5-yl 1-yl 6 A 1,1- 4-methylphenyl phenyl Odimethylprop- 1-yl 7 A 1-methyl-1- 4-methylphenyl phenyl O chloro-methylethyl 8 A t-butyl 4-methylphenyl 1-naphthyl O 198-199 9 A t-butyl4-methylphenyl 2-pyridinyl O 10 A t-butyl 4-methylphenyl benzyl S 11 At-butyl 4-CF₃-phenyl 1,2,3,4-tetra- O hydronaphth-2- yl 12 Acyclopentanyl 4-methylphenyl 4-cyano- O naphth-1-yl 13 A t-butyl3-fluoro-phenyl 5-iso-quinolinyl O 14 A t-butyl 4-methylphenyl phenyl O179-180 15 A t-butyl 4-methylphenyl 2-fluoro-phenyl O 103-104 16 At-butyl 4-methylphenyl 2-chloro-phenyl O 197.5-198   17 A t-butyl4-methylphenyl 4-cyano-2- O 180-181 ethylphenyl 18 A t-butyl4-methylphenyl 4-methoxy- O 209-210 phenyl 19 A t-butyl 4-methylphenyl3-methoxy- O 117-118 naphth-1-yl 20 A t-butyl 4-methylphenyl4-phenyl-napth- O 110-120 1-yl 21 A t-butyl 4-methylphenyl 4-cyanonapth-O 252-255 1-yl 22 A t-butyl 4-methylphenyl 4-chloronapth- O 194-195 1-yl23 A t-butyl methyl 4-chloronapth- O 230-231 1-yl 24 A t-butyl phenyl1,2,3,4-tetra- O 212-213 hydronapth-1- yl 25 A t-butyl phenyl 1-naphthylO 107 26 A t-butyl phenyl 3,4-methyl- O 221 enedioxy- phenyl 27 At-butyl phenyl 5-indanyl O 192 28 A t-butyl phenyl 2-chloro-4- O 131-132cyano-phenyl 29 A t-butyl 3-bromo- 4-fluoro-phenyl O 210-211 phenyl 30 At-butyl 4-cyanophenyl 2-chloro-phenyl O 184-185 31 A t-butyl4-CF₃-phenyl 2-fluoro-phenyl O 196-197 32 A t-butyl 3,4-dimethyl-4-fluoro-phenyl O 223-225 phenyl 33 A t-butyl 3-chloro-4- phenyl O 175methylphenyl 34 A t-butyl 3-nitrophenyl phenyl O 177-178 34 A t-butyl 3-phenyl O 184-185 dimethylamino- phenyl 35 A t-butyl 4-pyridinyl phenyl O178-180 36 A t-butyl 3-pyridinyl 4-cyclopentyl- O 204-206 napth-1-yl 37A t-butyl 2-methyl- 2-fluoro-phenyl O 108-110 pyridin-5-yl 38 A1-methyl- phenyl phenyl O 86-88 cyclohexan-1- yl 39 A 1-methyl- phenylphenyl O 161 cyclopropy-1-yl 40 A 1,1-dimethyl-2- phenyl phenyl O191-192 chloroethyl 41 A 1,1-dimethyl- phenyl phenyl O 175 propyl 42 A1-methyl- phenyl 2-chloro-phenyl O 84-86 tetrahydro- pyran-4-yl 43 At-butyl phenyl 4-chloro-phenyl S 164-166 44 B t-butyl phenyl4-chloro-phenyl O 199-200 45 B t-butyl phenyl 2-indanyl O 46 B 1-methyl-Pyridin-3-yl 1-naphthyl O cyclopent-1-yl 47 C hydrogen phenyl2,4-dichloro- O phenyl 48 C methyl phenyl 2-indanyl O 49 C hydrogenphenyl 4-chloro-phenyl O 143-144

ASSESSMENT OF BIOLOGICAL PROPERTIES

Inhibition of TNFα Production in THP Cells

The inhibition of TNFα production can be measured in lipopolysaccharidestimulated THP cells. All cells and reagents were diluted in RPMI 1640with phenol red and L-glutamine, supplemented with additionalL-glutamine (total: 4 mM), penicillin and streptomycin (50 units/mleach) and fetal bovine serum (FBS, 3%) (GIBCO, all conc. final). Theassay was performed under sterile conditions; only test compoundpreparation was nonsterile. Initial stock solutions were made in DMSOfollowed by dilution into RPMI 1640 2-fold higher than the desired finalassay concentration. Confluent THP.1 cells (2×10⁶ cells/ml, final conc.;American Type Culture Company, Rockville, Md.) were added to 96 wellpolypropylene round bottomed culture plates (Costar 3790; sterile)containing 125 μl test compound (2 fold concentrated) or DMSO vehicle(controls, blanks). DMSO concentration did not exceed 0.2% final. Cellmixture was allowed to preincubate for 30 min, 37° C., 5% CO₂ prior tostimulation with lipopolysaccharide (LPS; 1 μg/ml final; Sigma L-2630,from E.coli serotype 0111.B4; stored as 1 mg/ml stock in endotoxinscreened distilled H₂O at −80° C.). Blanks (unstimulated) received H₂Ovehicle; final incubation volume was 250 μl. Overnight incubation (18-24hr) proceeded as described above. The assay was terminated bycentrifuging plates 5 min, room temperature, 1600 rpm (400×g);supernatants were transferred to clean 96 well plates and stored −80° C.until analyzed for human TNFα by a commercially available ELISA kit(Biosource #KHC3015, Camarillo, Calif.). Data was analyzed by non-linearregression (Hill equation) to generate a dose response curve using SASSoftware System (SAS institute, Inc., Cary, N.C.). The calculated IC50value is the concentration of the test compound that caused a 50%decrease in TNFα production.

Representative compounds listed in the above Synthetic Examples wereevaluated and all had lC₅₀<10 μM in this assay.

Inhibition of Other Cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELISA kits for a particularcytokine, inhibition of IL-1 β, GM-CSF, IL-6 and IL-8 was demonstratedby representatives from Table 1.

What is claimed is:
 1. A compound of the formula I

wherein: the heterocyclic moiety

is selected from the group consisting of:

X is S, O or NR₆; Y is CHR₇ or N—H; R₁ is selected from the groupconsisting of: (a) C₃₋₁₀ branched alkyl, which is optionally partiallyor fully halogenated, and optionally substituted with one to threephenyl, naphthyl or heteroaryl independently selected from pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, isoxazolyl and isothiazolyl, each phenyl, naphthyl orheteroaryl group being substituted with 0 to 5 groups selected fromhalogen, C₁₋₆ branched or unbranched alkyl which is optionally partiallyor fully halogenated, C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, hydroxy,cyano, C₁₋₃ alkyloxy which is optionally partially or fully halogenated,aminocarbonyl and di(C₁₋₃)alkylaminocarbonyl; (b) a cycloalkyl groupselected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl,which cycloalkyl group is optionally partially or fully halogenated andwhich is optionally substituted with one to three C₁₋₃ alkyl groups, oran analog of said cycloalkyl group wherein instead of one to three ringmethylene groups there are groups independently selected from O, S,CHOH, >C═O, >C═S and NH; (c) C₃₋₁₀ branched alkenyl which is optionallypartially or fully halogenated, and which is optionally substituted withone to three groups independently selected from C₁₋₅ branched orunbranched alkyl, phenyl, naphthyl or heteroaryl independently selectedfrom pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, andeach phenyl, naphthyl or heteroaryl group being substituted with 0 to 5groups selected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, hydroxy, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl; (d) a cycloalkenyl group selected fromcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein saidcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups; (e) cyano; and, (f) an alkoxy carbonyl group selected frommethoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; R₂ is selected fromthe group consisting of hydrogen, C₁₋₆ branched or unbranched alkylwhich is optionally partially or fully halogenated, acetyl, benzoyl andphenylsulfonyl; R₃ is selected from the group consisting of: a) phenyl,naphthyl and heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl,wherein each phenyl, naphthyl or heteroaryl group is optionallysubstituted with one to five groups independently selected from C₁₋₆branched or unbranched alkyl, phenyl, naphthyl, heteroaryl selected fromthe group set forth immediately above, C₁₋₆ branched or unbranched alkylwhich is optionally partially or fully halogenated, cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl,halo, hydroxy, cyano, C₁₋₃ alkyloxy which is optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein theheteroaryl moiety is selected from the group set forth above in thissubparagraph, nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino,naphthylamino, heteroarylamino wherein the heteroaryl moiety is selectedfrom the group set forth above in this subparagraph, aminocarbonyl, amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄ branched or unbranched alkyloxycarbonyl, C₁₋₅ alkylcarbonyl C₁₋₄ branched or unbranched alkyl, aminoC₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino(C₁₋₅)alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl; b) fused aryl selected frombenzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, and fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene,wherein the fused aryl or fused heteroaryl ring is substituted with 0 to3 groups independently selected from phenyl, naphthyl and heteroarylselected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, halo, cyano, C₁₋₃ alkyloxy which is optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteroaryloxy wherein theheteroaryl moiety is selected from the group set forth above in thissubparagraph, nitro, amino, mono-or di-(C₁₋₃)alkylamino, phenylamino,naphthylamino, heteroarylamino wherein the heteroaryl moiety is selectedfrom the group set forth above in this subparagraph, aminocarbonyl, amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄ branched or unbranched alkyloxycarbonyl, C₁₋₅ alkylcarbonyl C₁₋₄ branched or unbranched alkyl, aminoC₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino (C₁₋₅)alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl; c) a cycloalkyl group selected fromcyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which cycloalkyl group is optionallypartially or fully halogenated and which is optionally substituted withone to three C₁₋₃ alkyl groups; d) a cycloalkenyl group selected fromcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein saidcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups; and, e) acetyl, benzoyl and phenylsulfonyl; or R₁ and R₂taken together optionally form a fused phenyl or pyridinyl ring; R₄ isnot present; R₅ is selected from the group consisting of: a) phenyl,naphthyl and heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl,wherein each phenyl, naphthyl or heteroaryl group optionally bears oneto five groups selected from phenyl, naphthyl and heteroaryl whereineach heteroaryl moiety is independently selected from the group definedabove in this subparagraph, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, halo, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy,nitro, amino, mono- or di- (C₁₋₃) alkylamino, phenylamino,naphthylamino, aminocarbonyl, mono- or di-(C₁₋₃) alkylaminocarbonyl,amino(C₁₋₅)alkyl or alkenyl, di- (C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl,phenylamino(C₁₋₃)alkyl or alkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl,phenylamido(C₁₋₃)alkyl or alkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl,phenyl(C₁₋₅)alkyl or alkenyl and naphthyl(C₁₋₅)alkyl or alkenyl; b)fused aryl selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl, and fused heteroaryl selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,cyclohexanobenzimidazole, cyclopentanobenzoxazole,cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole,cyclopentanothiophene and cyclohexanothiophene, wherein the fused arylor fused heteroaryl ring bears 0 to 3 groups selected from phenyl,naphthyl, heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyland isothiazolyl, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, halo, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy,nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino, naphthylamino,aminocarbonyl, mono-or di-(C₁₋₃) alkylaminocarbonyl, amino(C₁₋₅)alkyl oralkenyl, di-(C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl,phenylamino(C₁₋₃)alkyl or alkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl,phenylamido(C₁₋₃)alkyl or alkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl,phenyl(C₁₋₅)alkyl or alkenyl and naphthyl(C₁₋₅)alkyl or alkenyl; and, c)cycloalkyl selected from cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which cycloalkylgroup is optionally partially or fully halogenated and which isoptionally substituted with one to three C₁₋₃ alkyl groups; d)cycloalkenyl selected from cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl,which cycloalkenyl group is optionally partially or fully halogenatedand which is optionally substituted with one to three C₁₋₃ alkyl groups;and e) phenyl(C₁₋₅ branched or unbranched)alkyl, and naphthyl(C₁₋₅branched or unbranched)alkyl, wherein the phenyl or naphthyl ring issubstituted with 0 to 5 groups selected from the group consisting ofphenyl, naphthyl, heteroaryl selected from pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl and isothiazolyl, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, halo, cyano, C₁₋₃ alkyloxywhich is optionally partially or fully halogenated, phenyloxy,naphthyloxy or heteroaryloxy wherein the heteroaryl moiety is as definedabove in this subparagraph; R₆ is hydrogen, cyano or C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated;and, R₇ is hydrogen or C₁₋₆ branched or unbranched alkyl, which isoptionally partially or fully halogenated; or a tautomer orpharmaceutically acceptable salt thereof.
 2. A compound of the formula Iaccording to claim 1, wherein: Y is N—H; R₁ is selected from the groupconsisting of: a) C₃₋₁₀ branched alkyl, which is optionally partially orfully halogenated, and optionally substituted with one to three phenyl,naphthyl or heteroaryl independently selected from pyridinyl andthienyl, each phenyl, naphthyl or heteroaryl being substituted with 0 to5 groups selected from halogen, C₁₋₆ branched or unbranched alkyl whichis optionally partially or fully halogenated, C₃₋₈ cycloalkyl, C₅₋₈cycloalkenyl, hydroxy, cyano, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, aminocarbonyl anddi(C₁₋₃)alkylaminocarbonyl; b) a cycloalkyl group selected fromcyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which cycloalkylgroup is optionally partially or fully halogenated and which isoptionally substituted with one to three C₁₋₃ alkyl groups, or an analogof said cycloalkyl group wherein instead of one to three ring methylenegroups there are groups independently selected from O, S,CHOH, >C═O, >C═S and NH; c) C₃₋₁₀ branched alkenyl which is optionallypartially or fully halogenated, and which is optionally substituted withone to three groups independently selected from C₁₋₅ branched orunbranched alkyl, phenyl, naphthyl or heteroaryl independently selectedfrom pyridinyl and thienyl and each phenyl, naphthyl or heteroaryl groupbeing substituted with 0 to 5 groups selected from halogen, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl,hydroxy, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, aminocarbonyl and mono- or di(C₁₋₃)alkylaminocarbonyl; d) acycloalkenyl group selected from cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl andbicycloheptenyl, wherein each cycloalkenyl group is optionallysubstituted with one to three C₁₋₃ alkyl groups; e) an alkoxy carbonylgroup selected from methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;R₂ is selected from the group consisting of hydrogen, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,acetyl, benzoyl and phenylsulfonyl; R₃ is selected from the groupconsisting of: a) phenyl, naphthyl and heteroaryl selected frompyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl and benzoxazolyl,wherein each phenyl, naphthyl or heteroaryl group is optionallysubstituted with one to three groups independently selected from C₁₋₆branched or unbranched alkyl, phenyl, naphthyl, heteroaryl selected fromthe group set forth immediately above, C₁₋₆ branched or unbranched alkylwhich is optionally partially or fully halogenated, cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl,halo, hydroxy, cyano, C₁₋₃ alkyloxy which is optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein theheteroaryl moiety is selected from the group set forth above in thissubparagraph, nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino,naphthylamino, heteroarylamino wherein the heteroaryl moiety is selectedfrom the group set forth above in this subparagraph, aminocarbonyl, amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄ branched or unbranched alkyloxycarbonyl, C₁₋₅ alkylcarbonyl C₁₋₄ branched or unbranched alkyl, aminoC₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino(C₁₋₅)alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl; b) fused aryl selected frombenzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, and fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanothiophene and cyclohexanothiophene, wherein the fused arylor fused heteroaryl ring is substituted with 0 to 3 groups independentlyselected from phenyl, naphthyl and heteroaryl selected from pyridinyland thienyl, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, halo, cyano, C₁₋₃ alkyloxy which isoptionally partially or fuilly halogenated, phenyloxy, naphthyloxy,heteroaryloxy wherein the heteroaryl moiety is selected from the groupset forth above in this subparagraph, amino, mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heteroarylamino whereinthe heteroaryl moiety is selected from the group set forth above in thissubparagraph, aminocarbonyl, a mono- or di-(C₁₋₃)alkyl aminocarbonyl,C₁₋₄ branched or unbranched alkyl oxycarbonyl, C₁₋₅ alkylcarbonyl C₁₋₄branched or unbranched alkyl, amino C₁₋₅ alkyl, mono- ordi-(C₁₋₃)alkylamino(C₁₋₅)alkyl, aminosulfonyl,di-(C₁₋₃)alkylaminosulfonyl; c) a cycloalkyl group selected fromcyclopentanyl, cyclohexanyl and cycloheptanyl, which cycloalkyl group isoptionally partially or fully halogenated and which is optionallysubstituted with one to three C₁₋₃ alkyl groups; d) a cycloalkenyl groupselected from cyclopentenyl, cyclohexenyl and cycloheptenyl, whereinsaid cycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups; and, e) acetyl, benzoyl and phenylsulfonyl; or R₂ and R₃taken together optionally form a fused phenyl or pyridinyl ring; R₅ isselected from the group consisting of: a) phenyl, naphthyl andheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrazolyl, thienyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, wherein each phenyl,naphthyl or heteroaryl group optionally bears one to three groupsselected from phenyl, naphthyl and heteroaryl wherein each heteroarylmoiety is independently selected from the group defined above in thissubparagraph, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, halo, cyano, C₁₋₃ alkyloxy which is optionally partiallyor fully halogenated, phenyloxy, naphthyloxy, mono-or di- (C₁₋₃)alkylamino, phenylamino, naphthylamino, mono- or di-(C₁₋₃)alkylaminocarbonyl, amino(C₁₋₅)alkyl or alkenyl,di-(C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl, phenylamino(C₁₋₃)alkyl oralkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamido(C₁₋₃)alkyl oralkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl, phenyl(C₁₋₅)alkyl oralkenyl and naphthyl(C₁₋₅)alkyl or alkenyl; b) fused aryl selected frombenzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, and fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanothiophene and cyclohexanothiophene, wherein the fused arylor fused heteroaryl ring bears 0 to 3 groups selected from phenyl,naphthyl, heteroaryl selected from pyridinyl and thienyl, C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, amino, mono- or di- (C₁₋₃)alkylamino, phenylamino, naphthylamino, aminocarbonyl, mono- ordi-(C₁₋₃) alkylaminocarbonyl, amino(C₁₋₅)alkyl or alkenyl,di-(C₁₋₃)alkylamino(C₁₋₅)alkyl or alkenyl, phenylamino(C₁₋₃)alkyl oralkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamido(C₁₋₃)alkyl oralkenyl, naphthylamido(C₁₋₃)alkyl or alkenyl, phenyl(C₁₋₅)alkyl oralkenyl and naphthyl(C₁₋₅)alkyl or alkenyl; c) cycloalkyl selected fromcyclopentanyl, cyclohexanyl and cycloheptanyl, which cycloalkyl group isoptionally partially or fully halogenated and which is optionallysubstituted with one to three C₁₋₃ alkyl groups; d) cycloalkenylselected from cyclopentenyl and cyclohexenyl, which cycloalkenyl groupis optionally partially or fully halogenated and which is optionallysubstituted with one to three C₁₋₃ alkyl groups; and e) phenyl(C₁₋₅branched or unbranched)alkyl, and naphthyl(C₁₋₅ branched orunbranched)alkyl, wherein the phenyl or naphthyl ring is substitutedwith 0 to 5 groups selected from the group consisting of phenyl,naphthyl, heteroaryl selected from pyridinyl and thienyl, C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy or heteroaryloxy wherein theheteroaryl moiety is as defined above in this subparagraph; and R₆ ishydrogen, cyano or C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated.
 3. A compound of the formula I accordingto claim 2, wherein: the heterocyclic moiety

X is S or O; Y is N—H; R₁ is selected from the group consisting of: a)C₃₋₇ branched alkyl, which is optionally partially or fully halogenated,and optionally substituted with one to three phenyl or heteroarylindependently selected from pyridinyl and thienyl, each phenyl orheteroaryl group being substituted with 0 to 3 groups selected fromhalogen, C₁₋₆ branched or unbranched alkyl which is optionally partiallyor fully halogenated, C₃₋₈ cycloalkyl and C₁₋₃ alkyloxy which isoptionally partially or fully halogenated; b) a cycloalkyl groupselected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl,which cycloalkyl group is optionally partially or fully halogenated andwhich is optionally substituted with one to three C₁₋₃ alkyl groups; C)C₃₋₇ branched alkenyl which is optionally partially or fullyhalogenated, and which is optionally substituted with one to threegroups independently selected from C₁₋₅ branched or unbranched alkyl,phenyl or heteroaryl independently selected from pyridinyl and thienyland each phenyl or heteroaryl group being substituted with 0 to 3 groupsselected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl and C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated; R₃ is selected from the group consisting of: a) phenyl,naphthyl and heteroaryl selected from pyridinyl, quinolinyl andisoquinolinyl, wherein each phenyl, naphthyl or heteroaryl group isoptionally substituted with one to three groups independently selectedfrom C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, heteroarylselected from the group set forth immediately above, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, halo, hydroxy,cyano, C₁₋₃ alkyloxy which is optionally partially or fully halogenated,phenyloxy, heteraryloxy wherein the heteroaryl moiety is selected fromthe group set forth above in this subparagraph, mono- ordi-(C₁₋₃)alkylamino, phenylamino, heteroarylamino wherein the heteroarylmoiety is selected from the group set forth above in this subparagraph,aminocarbonyl, a mono- or di-(C₁₋₃)alkyl aminocarbonyl and mono- ordi-(C₁₋₃)alkylamino(C₁₋₅)alkyl; b) fused aryl selected frombenzocyclobutanyl, indanyl, indenyl, dihydronaphthyl andtetrahydronaphthyl, and fused heteroaryl selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanothiophene andcyclohexanothiophene, wherein the fused aryl or fused heteroaryl ring issubstituted with 0 to 3 groups independently selected from phenyl andheteroaryl selected from pyridinyl and thienyl, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy, heteroaryloxy wherein the heteroaryl moiety isselected from the group set forth above in this subparagraph, mono- ordi-(C₁₋₃)alkylamino, phenylamino, heteroarylamino wherein the heteroarylmoiety is selected from the group set forth above in this subparagraph,aminocarbonyl, a mono- or di-(C₁₋₃)alkyl aminocarbonyl and mono- ordi-(C₁₋₃)alkylamino(C₁₋₅)alkyl; c) a cycloalkyl group selected fromcyclopentanyl, cyclohexanyl and cycloheptanyl, which cycloalkyl group isoptionally partially or fully halogenated and which is optionallysubstituted with one to three C₁₋₃ alkyl groups; d) acetyl, benzoyl andphenylsulfonyl; and, R₁ is selected from the group consisting of: a)phenyl, naphthyl and heteroaryl selected from pyridinyl, thienyl,quinolinyl and isoquinolinyl, wherein each phenyl, naphthyl orheteroaryl group optionally bears one to three groups selected fromphenyl and heteroaryl wherein each heteroaryl moiety is independentlyselected from the group defined above in this subparagraph, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, halo,cyano, C₁₋₃ alkyloxy which is optionally partially or fully halogenated,phenyloxy, phenylamino; b) fused aryl selected from benzocyclobutanyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl and benzocycloheptenyl, and fused heteroaryl selectedfrom cyclopentenopyridine, cyclohexanopyridine, cyclopentanothiopheneand cyclohexanothiophene, wherein the fused aryl or fused heteroarylring bears 0 to 3 groups selected from phenyl, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy and phenylamino; and c) phenyl(C₁₋₅ branched orunbranched)alkyl, and naphthyl(C₁₋₅ branched or unbranched)alkyl,wherein the phenyl or naphthyl ring is substituted with 0 to 3 groupsselected from the group consisting of phenyl, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated and phenyloxy.
 4. A compound of the formula I according toclaim 1, wherein: the heterocyclic moiety

X is S or O; Y is N—H; R₁ is selected from the group consisting of: a)C₃₋₁₀ branched alkyl, which is optionally partially or fully halogented,and optionally substituted with one to three phenyl, naphthyl orheteroaryl groups independently selected from pyridinyl and thienyl,each such phenyl, naphthyl or heteroaryl group being substituted with 0to 3 groups selected from halogen, C₁₋₆ branched or unbranched alkylwhich is optionally partially or fully halogenated, C₃₋₈ cyloalkyl,hydroxy, cyano and C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated; b) a cycloalkyl group selected from cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which cycloalkyl group is optionallypartially or fully halogenated and which is optionally substituted withon to three C₁₋₃ alkyl groups, or an analog of such cycloalkyl groupwherein instead of one to three ring methylene groups there are groupsindependently selected from O,S, CHOH,>C═O,>C═C and NH; c) C₃₋₁₀branched alkenyl which is optionally partially or fully halogenated, andwhich is optionally substituted with one to three groups independentlyselected from C₁₋₅ branched or unbranched alkyl, phenyl, naphthyl orheteroaryl independently selected from pyridinyl and thienyl and eachsuch phenyl, naphthyl or heteroaryl group being substituted with 0 to 3groups selected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl, hydroxy, cyano, and C₁₋₃ alkyloxy which is optionallypartially or fully halogenated; d) a cycloalkenyl group selected fromcyclopentenyl, cyclohexenyl, bicyclohexenyl and bicycloheptenyl, whereinsuch cycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups; e) an alkoxy carbonyl group selected from methoxycarbonyl,ethoxycarbonyl and propoxycarbony; R₂ is selected from the groupconsisting of: hydrogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, acetyl, benzoyl andphenylsulfonyl; R₃ is selected from the group consisting of: a) phenyl,naphthyl and heteroaryl selected from pyridinyl, quinolinyl andisoquinolinyl, wherein such phenyl, naphthyl or heteroaryl group isoptionally substituted with one to three groups independently selectedfrom C₁₋₆ branched or branched alkyl, phenyl, naphthyl, heteroarylselected from the group set forth immediately above, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, phenyl C₁₋₅ alkyl,halo, hydroxy, cyano, C₁₋₃ alkyloxy which is optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein theheteroaryl moiety is selected from the group set forth above in thissubparagraph, mono- or di-(C₁₋₄)alkylamino, phenylamino, naphthylamino,heteroarylamino wherein the heteroaryl moiety is selected from the groupset forth above in this subparagraph, aminocarbonyl, a mono- ordi-(C₁₋₃)alkyl aminocarbonyl, (C₁₋₅ alkylcarbonyl C₁₋₄ branched orunbranched alkyl, amino C₁₋₅ alkyl and mono- or di-(C₁₋₃)alkylamino(C₁₋₅)alkyl; b) fused aryl selected from benzocyclobutanyl,indanyl, indenyl, dihydronaphthyl and tetrahydronaphthyl, and fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanothiophene and cyclohexanothiophene, wherein the fused arylor fused heteroaryl ring is substituted with 0 to 3 groups independentlyselected from phenyl, naphthyl and heteroaryl selected from pyridinyland thienyl, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, halo, cyano, C₁₋₃ alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy,heteroaryloxy wherein the heteroaryl moiety is selected from the groupset forth above in this subparagraph, mono- or di-(C₁₋₃) alkylamino,phenylamino, naphthylamino, heteroarylamino wherein the heteroarylmoiety is selected from the group set forth above in this subparagraph,aminocarbonyl, a mono- or di-(C₁₋₃)alkyl aminocarbonyl, amino C₁₋₅ alkyland mono- or di-(C₁₋₃)alkylamino(C₁₋₅)alkyl; c) a cycloalkyl groupselected from cyclopentanyl, cyclohexanyl and cycloheptanyl, whichcycloalkyl group is optionally partially or fully halogenated and whichis optionally substituted with one to three C₁₋₃ alkyl groups; d) acycloalkenyl group selected fro cyclopentenyl, cyclohexenyl andcycloheptenyl, wherein such cycloalkenyl group is optionally substitutedwith one to three C₁₋₃ alkyl groups; e) acetyl, benzoyl andphenylsulfonyl; and, or R₁ and R₂ taken together optionally form a fusedphenyl or pyridinyl ring, R₅ is selected from the group consisting of:a) phenyl, naphthyl and heteroaryl selected from pyridinyl, thienyl,quinolinyl, isoquinolinyl and indolyl, wherein such phenyl, naphthyl orheteroaryl group optionally bears one to three groups selected fromphenyl, naphthyl and heteroaryl wherein each such heteroaryl moiety isindependently selected from the group defined above in thissubparagraph, C₁₋₆ branched or unbranched alkyl which is optionallypartially of fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, halo, cyano, C₁₋₃ alkyloxy which is optionally partiallyor fully halogenated, phenyloxy, naphthyloxy,, phenylamino,naphthylamino phenylamino(C₁₋₃)alkyl or alkenyl,naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamido(C₁₋₃)alkyl or alkenyl,naphthylamido(C₁₋₃)alkyl or alkenyl, heteroarylamido(C₁₋₃)alkyl oralkenyl wherein the heteroaryl moiety is as defined above in thissubparagraph; b) fused aryl selected from benzocyclobutanyl, indanyl,indenyl, dihydronaphtyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl, and fused heteroaryl selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanothiophene andcyclohexanothiophene, wherein the fused aryl or fused heteroaryl ringbears 0 to 3 groups selected from phenyl, naphthyl, heteroaryl selectedfrom pyridinyl and thienyl, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, halo, cyano, C₁₋₃ alkyloxywhich is optionally partially or fully halogenated, phenyloxy,naphthyloxy, phenylamino, naphthylamino, phenylamino(C₁₋₃)alkyl oralkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl, phenylamino(C₁₋₃)alkyl oralkenyl, naphthylamino(C₁₋₃)alkyl or alkenyl, heteroarylamido(C₁₋₃)alkylor alkenyl wherein the heteroaryl moiety is as defined above in thissubparagraph; and c) phenyl(C₁₋₅ branched or unbranched, andnaphthyl(C₁₋₅ branched or unbranched)alkyl, wherein the phenyl ornaphthyl ring is substituted with 0 to 3 groups selected from the groupconsisting of phenyl, naphthyl, heteroaryl selected from pyridinyl andthienyl, C₁₋₆ branched or unbranched alkyl which is optionally partiallyor fully halogenated, halo, cyano, C₁₋₃ alkyloxy which is optionallypartially of fully halogenated, phenyloxy, naphthyloxy or heteroaryloxywherein the heteroaryl moiety is as defined above in this subparagraph.5. A pharmaceutical composition comprising a compound according to claim1 and a pharmaceutically acceptable carrier.
 6. A method for treating adisease or pathological condition involving inflammation comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound in accordance with claim
 1. 7. The methodaccording to claim 6 wherein the pathological condition is a chronicinflammatory disease.
 8. The method according to claim 6 wherein thepathological condition is an acute inflammatory disease.
 9. A method ofreducing undesirable levels of one or more of the cytokines TNFα, IL-1β,GM-CSF, IL-6, or IL-8 comprising administering to a host atherapeutically effective amount of a compound in accordance withclaim
 1. 10. A method treating a disease selected from the groupconsisting of adult respiratory distress syndrome (ARDS), Alzheimer'sdisease, Crohn's disease, type I diabetes, type II diabetes, graft vs.host reaction, inflammatory bowel disease, multiple sclerosis,myocardial infarction, osteoarthritis, osteoporosis, psoriasis,rheumatoid arthritis, stroke, sepsis, septic shock, toxic shock syndromeand ulcerative colitis, comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound inaccordance with claim
 1. 11. A compound of the formula

wherein the heterocyclic moiety:

R₂ is not present and R₁, R₃, R₅ and X are selected from: R₁ R₃ R₅ Xhydrogen phenyl 2,4-dichloro- O phenyl methyl phenyl 2-indanyl Ohydrogen phenyl 4-chloro-phenyl O

or a tautomer or pharmaceutically acceptable salt thereof.